Idiopathic pulmonary arterial hypertension (IPAH) is a progressive disease that leads to deterioration in cardiopulmonary function and premature death. Metabolic dysregulation has emerged as a major area of research in the pathobiology of IPAH, including the altered bioavailability of nitric oxide (NO) and dysregulated glucose metabolism. Several processes may be governed by the metabolic dysfunction present in IPAH, including enhanced pulmonary vascular cell proliferation and vasoconstriction. Our long-term goal is to understand the role of the metabolic abnormalities in IPAH pathogenesis in order to design therapeutic interventions for the disease. Our effectiveness to design therapies in IPAH will be enhanced by understanding the link between glucose dysregulation, aberrant cell proliferation, and NO deficiency in the human disease and experimental animal models. The central hypothesis of this proposal is that abnormal glucose utilization and flux through the hexosamine biosynthetic pathway (HBP) drives cell proliferation and NO deficiency in IPAH. The hypothesis has been formulated based on our already published studies and recently generated preliminary data in humans and animal models. Our rationale for the proposed research is designed to establish the effects of glucose key metabolic dysregulation in IPAH by focusing on the rate-limiting OGT/O- GlcNAc axis of the HBP. Mechanistic insights will be gained by studying the HBP in animal models of the disease. The potential of this axis as a therapeutic target in IPAH will be tested by evaluating whether the OGT/O-GlcNAc axis and disease outcomes are modifiable by diet and exercise. Thus, we will test this hypothesis by pursuing the following specific aims: AIM 1) Determine the mechanistic role of the OGT/O- GlcNAc axis in cell proliferation in IPAH and experimental animal models of the disease; AIM 2) Investigate the specific molecular regulation of eNOS activity by O-GlcNAc in IPAH pathogenesis; and AIM 3) Establish glucose metabolic dysregulation as a modifiable marker of clinical outcomes in IPAH. The proposed research is significant because it will: (i) establish glucose dysregulation, through the HBP and the OGT/O-GlcNAc axis as the driver for the abnormal pulmonary vascular cell proliferation; (ii) determine the extent to which these metabolic abnormalities correlate with IPAH severity and outcomes, and (iii) establish an exercise and diet intervention as a means of improving disease outcomes.